Role of the Gut Microbiota in Autoimmunity

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1 Role of the Gut Microbiota in Autoimmunity Pavan Bhargava, MD - Neuroimmunology Fellow Division of Neuroimmunology and Neurological Infections Johns Hopkins University, Baltimore, MD. May, 2015 None Disclosures

2 Outline Gut microbiota basics Functions of the gut microbiota Gut microbiota in MS models Gut microbiota in MS Diet and the gut microbiota Future directions Gut microbiota Gut microbiota : population of microbes (bacteria, archaea, viruses, and fungi) found in the gut Gut microbiome : collective genome of microbes inhabiting the human gut The number of bacteria and their genetic material exceed the number of cells in our body and our genetic material by a factor of 10 and a 100 respectively

3 Gut microbiota Fetal gut is sterile and is colonized at the time of birth Microbiota evolve with age and increase in diversity till adolescence, after which they remain fairly stable until old age Peterson CT et al. Clin Exp Immunol, 179: Methods to characterize the gut microbiota Bhargava P & Mowry EM. Curr Neurol Neurosci Rep, 2014 Oct;14(10): 492.

4 Gut microbiome enterotypes M Arumugam et al. Nature 000, 1-7 (2011) Gut enterotypes may have functional differences M Arumugam et al. Nature 000, 1-7 (2011)

5 Gut microbiome more layers of complexity Microbiota vary from stomach to colon Between ileum and colon there is a shift from aerobes to anaerobes Additionally there is a spatial distribution within the colon from mucosal surface to lumen FUNCTIONS OF THE GUT MICROBIOTA

6 Functions of the gut microbiota Metabolic functions - Bile acid metabolism - SCFA production - Trophic effects Immune functions - Formation of gut associated lymphoid tissue - Th17/ Treg balance - Effects on dendritic cells, B cells and mononuclear cells Immunological functions of the gut microbiota Longman RS et al. Cold Spring Harb Symp Quant Biol. 2013; 78:

7 Effects of gut microbiota metabolites Lee WJ & Hase K. Nat Chem Biol, June GUT MICRIOBIOTA IN MODELS OF MS

8 Oral antibiotic treatment changes reduces the severity of EAE Ochoa-Reparaz J et al. J Immunol, 2009; 183(10):6041. Oral antibiotic treatment ameliorates EAE through increase in T reg cells Ochoa-Reparaz J et al. J Immunol, 2009; 183(10):6041.

9 Antibiotic treatment induces CD11c high CD103+ DCs that drive the formation of T reg cells Ochoa-Reparaz J et al. J Immunol, 2009; 183(10):6041. Germ Free mice develop less severe EAE Yun Kyung Lee et al. PNAS 2011;108:

10 Inflammation is attenuated in GF mice on EAE induction with an increase in T reg cells Yun Kyung Lee et al. PNAS 2011;108: SFBs promote pro-inflammatory T cell responses outside the gut during EAE Yun Kyung Lee et al. PNAS 2011;108:

11 Commensal microbiota are required for the development of spontaneous EAE K Berer et al. Nature 000, 1-4 (2011) Effect of microbiota on T-cell activation and their cytokine profiles in the GALT K Berer et al. Nature 000, 1-4 (2011)

12 B-cell recruitment is impaired in germ-free RR mice K Berer et al. Nature 000, 1-4 (2011) Treatment with PSA derived from Bacteroides fragilis reduces the severity of EAE Ochoa-Reparaz J et al. Mucosal Immunol, 2010 Sep; 3(5): 487

13 PSA up-regulates CD39 signaling through TLR2 Wang Y et al. Nature Communications, 2014 Jul 21; 5: Summary Gut microbiota play a role in development of Th17 cells Modulation of the gut microbiota using antibiotics changes the susceptibility to EAE This may be mediated through DC and B cell populations A bacterial polysaccharide can reduce the severity of EAE These observation suggest that the gut microbiota may play an important role in MS

14 GUT MICROBIOME IN MS Clostridium perfringens type B in MS 21 year-old woman with first clinical demyelinating event : C. perfringens type B in her stool Lower prevalence of C. perfringens type A in MS compared to HCs and increased reactivity to ETX in MS patients (10% vs 1%) Rumah KR et al. PLOS one, 2013; 8(10):e76359

15 Gut microbiome in MS Pilot study of 15 subjects (8 MS and 7 healthy control) Less Feacalibacterium OTUs, Bacteroidaceae OTUs and more Ruminococcus OTUs were seen in the MS group Comparing treated to untreated patients there was a difference in Feacalibacterium, Bacteroidaceae, Ruminococcus, Lactobacillaceae Clostridium and other Clostridiales Cantarel BL et al. Journal of Investigative Medicine, 2015 June; 63(5):1 Effect of Glatiramer Acetate treatment on gut microbiome Cantarel BL et al. Journal of Investigative Medicine, 2015 June; 63(5):1

16 Effect of Vitamin D supplementation on the gut microbiota Cantarel BL et al. Journal of Investigative Medicine, 2015 June; 63(5):1 Other recent studies of gut microbiome in MS Increase in archaea (Methanobrevibacter) in MS patients, also a decrease in Butyricimonas (phylum Bacteroidetes) and Lachnospiracea (phylum Firmicutes) In a study of 43 MS patients those with higher vitamin D levels (>40 ng/ml) had increased Ruminococcaceae in the gut 1. Jhangi S et al. AAN annual meeting 2014 Philadelphia, PA. 2. Tankou S et al. AAN annual meeting 2015 Washington DC.

17 Pediatric MS and the gut microbiome 18 MS and 17 healthy controls Lachnospira, Ruminococcaceae, Paraprevotella were depleted and Bilophila, Bifidobacterium, Clostridiales, Coriobacteriaceae and Desulfovibrio were enriched in MS patients Finding also appeared to be affected by exposure to immunomodulatory therapy Tremlett H et al. AAN annual meeting 2015 Washington DC MS Microbiome Consortium 55 RRMS untreated, 37 on GA treatment and 55 control Enterobacter Akkermansia Fold difference vs. FDR-adjusted p-value Normalized relative abundance Control Tx naive -log10 FDR-adjustedp-value Glatiramer Examples of Differences in Relative Abundance (L6 level) log2 fold difference Katz-Sand I et al. AAN Annual meeting 2015 at Washington DC.

18 Summary There appear to be indications that certain bacterial taxa differ in abundance between MS and healthy controls DMT use appears to impact microbiota and should be accounted for in future studies Larger studies are required to replicate and validate findings that have been noted in preliminary studies of the microbiome in MS DIET AND THE GUT MICROBIOME

19 Long term diet is linked to gut enterotype Gary D. Wu et al. Science 2011;334: Diet can rapidly alter gut microbiome LA David et al. Nature 000, 1-5 (2013)

20 Effect of diet on gut micriobiota LA David et al. Nature 000, 1-5 (2013) Changes in the fecal concentration of bile acids and biomarkers for Bilophila on animal-diet LA David et al. Nature 000, 1-5 (2013)

21 Summary Long term diet affects gut microbiota composition A change in diet can produce changes in the microbiota within 24 hours of the nutrients reaching the gut Short term changes in diet can lead to a significant alterations in the microbiota that can have functional consequences Studies to evaluate the effect of diet on the microbiota in MS patients are required FUTURE DIRECTIONS

22 Humanized mice Germ free mice can be repopulated with human microbiota Following treatment with antibiotics and antifungals mice can be repopulated with microbiota of MS patients and healthy controls An important tool to study the effect of the MS microbiome on disease pathogenesis Hintze KJ et al. Gut Microbes, 2014; 5: 183. Fecal transplantation Utilized currently for severe C. difficile diarrhea very effective May be a means of altering dysbiotic gut microbiota Recent trial of FMT in Ulcerative colitis had encouraging results (24% remission in FMT group vs 5% in placebo) Moayyedi et al. Gastroenterology, April 2015;

23 Probiotics Would need to be specific for disease state Sustained effect on the microbiota and their functional characteristics A mix of 17 Clostridial species reduced the severity of experimental colitis by increasing the number of T reg cells KAtarashiet al. Nature 000, 1-5 (2013) Conclusions The gut microbiota have an important physiological role Gut micriobiota alterations can have profound effects in the animal models of MS Early studies suggest alterations in the gut microbiota in MS and an effect of DMTs on gut microbiota Several strategies to alter the gut microbiota and impact autoimmune disease are under investigation

24 THANK YOU